Immunity against bacteria and fungi

Immunity against bacteria and fungi.
Bacteria are microbes that are much more complex than viruses and are capable of replicating autonomously (independent of the machinery of the body’s cells). From an immunological point of view we can divide bacteria into two large groups: intracellular bacteria and extracellular bacteria. Some bacteria have very little or no invasive capacity and generally do not go beyond the epithelium and can generate pathology by secretion of toxins that if they can have systemic effects. Intracellular bacteria are the opposite example to the previous ones, since they have a high invasive capacity and fulfill their life cycle within the host cells, generally in macrophages.1

The mechanisms of bacterial replication, infection and pathogenicity are what will condition the most effective type of response to a bacterial infection.
Although there are a large number of species of fungi, only a few are pathogenic to humans. The majority of fungal infections occur in immunocompromised persons or because they are undergoing chemotherapy or immunosuppressive treatments.1
Little is known about the specific immune response against fungi, but in general terms we can consider that the mechanisms are common against bacteria.1

Innate response
These microbes are very complex antigenically and evolution has developed multiple mechanisms for the immune system to recognize them using innate response receptors that recognize molecular patterns associated with pathogens (PAMP), such as, for example, lipopolysaccharide present in Gram- bacteria.1

The innate humoral immune response against bacteria and fungi is mediated by the alternative pathway and the complementeo lectins pathway. The activation of these complement pathways occurs spontaneously on the surface of certain prokaryotic cells, producing the activation and deposition of complement terminal components on the bacterial surface and subsequent cell lysis. In addition to this effect, complement activation produces the release of anaphyllotoxins that induce inflammation and the attraction of cells to the focus of infection. Phagocytes can be activated by membrane receptors that recognize PAMPs or by opsonization receptors that will recognize complement factors C3b and C4b that are deposited on the microbe after complement activation. The phagocytes, once internalized, will set in motion the bactericidal mechanisms that destroy pathogens.1

Finally, phagocytes activated by their phagocyte and anaphyllotoxin receptors will release pro-inflammatory cytokines such as IL1, TNF-alpha, IL-6 and various chemokines that will contribute to the activation of endothelial cells to produce cell inflammation and extravasation. Stimulated phagocytes can also produce IL-12 which in turn stimulates NK lymphocytes that respond by synthesizing IFN-gamma, which in turn stimulates phagocytes facilitating the elimination of bacteria that have phagocyted.1

Adaptive response
In most cases, innate immunity through phagocytes is able to control the initial stages of bacterial and fungal infections. In the event that the innate response is not sufficient, the adaptive response will be triggered by activating specific T and B lymphocyte clones. The defensive role of antibodies against bacterial and fungal infections includes different mechanisms. Neutralizing antibodies (IgG and IgA isotypes) can bind to bacteria preventing their adhesion to cells or tissues that are otherwise colonized by microbes. In the case of non-invasive exotoxin-producing bacteria, it will suffice to produce neutralizing antibodies against toxins to block their pathogenic effect. The antibodies can also induce indirect responses by activating the complement (IgM, IgG) by the classical route, which will lead to the activation of terminal factors and bacterial lysis. Antibodies attached to the microbial surface can also activate phagocytosis by binding the immunoglobulins to Fc receptors.1

Finally, the phagocytes thus activated produce proinflammatory cytokines that will help coordinate the defensive response. The activation capacity of globulins is much higher than that achieved by the innate receptors of these same phagocytes, so if we have preformed antibodies against a microbe our immune response will be much more effective.1

Th lymphocytes play a very important role in coordinating the adaptive response to bacteria and fungi. On the one hand, Th lymphocytes are important in T-B cooperation for differentiation of B lymphocytes to antibody-producing plasma cells, especially in IgG and IgA responses. On the other hand, the cytokines secreted by Th1 lymphocytes are important for producing inflammation and activation of phagocytes. In general, the adaptive response to low invasive extracellular bacteria with pathogenicity by toxins such as Corynebacteium diphteriae or Vibrio cholerae is directed mainly by neutralizing antibodies. The response to more invasive bacteria such as Neisseria menningitidis or Staphylococcus aureus is based on the response by antibodies that activate complement and produce opsonization that efficiently activates the phagocytosis of the pathogen.1

Some bacteria, such as Mycobacterium tueberculosis or Mycobacterium leprae, have specialized in surviving within phagocytes, especially macrophages. To do this, they have developed characteristics that make them very resistant to the bactericidal mechanisms of phagocytes, protecting themselves from the antibodies that are in the extracellular medium. The immune response to these bacteria is more similar to that which is set in motion against viruses, so it requires the activation of T lymphocytes. The macrophages infected by these bacteria present, through class II HLA molecules, peptides derived from them to Th1 lymphocytes that respond by producing cytokines, especially IFN-gamma, which will bind to its receptor on the surface of the macrophage. Activation of the IFN-gamma-dependent macrophage secreted by the Th1 lymphocyte and direct cell contact signals via CD40-CD40L are essential for the elimination of most intracellular bacteria. In addition, macrophages and dendritic cells are capable of presenting mycobacterial lipids through CD1 molecules to special T-lymphocyte subtypes, such as NKT lymphocytes. NKT lymphocytes are capable of killing cells infected by intracellular bacteria, preventing their dissemination. Adeaás, secrete cytokines such as IFN-gamma and also release granulisine, an antibiotic capable of killing intracellular bacteria. On the other hand, Tc lymphocytes are also capable of killing infected cells by some types of cytoplasmic intracellular bacteria, such as Lysteria or Salmonella whose peptides are presented to Tc lymphocytes by MHC class I molecules1

Mechanisms of bacterial evasion against the immune response
Like viruses, some bacteria have developed mechanisms that allow them to evade the immune response. The generation of antigenic variants is one of these mechanisms used by bacteria such as Neisseria meningiditis, Neisseria ghonorreae or bacteria of the genus Borrelia (the cause of Lyme disease) that have different copies of the genes that encode the most antigenic proteins and that express randomly to escape the action of antibodies. Many bacterial species have developed mechanisms to prevent complement action, through proteins that prevent the deposition of complement terminator components, that mimic human complement regulatory proteins, or that have proteases that inactivate complement components once activated. Intracellular bacteria are able to live inside macrophages and other phagocytic cells because they have a mechanism that interferes with their activation. Some bacteria, such as Mycobacterium tuberculosis, once phagocytes prevent fusion between the phagosome and the lysosome.1

They can also inhibit the proton pump necessary for the acidification of the phagosome. Others, such as staphylococci, produce catalase that breaks down hydrogen peroxide (hydrogen peroxide), thus preventing its bactericidal power. Mycobacterium leprae has a very resistant external cover in which it has phenolytic compounds that inactivate the free radicals generated in the phagolysosome. Brucella abortus is able to inhibit the presentation of antigens by MHC class II, thus preventing collaboration between phagocytes and Th lymphocytes. Some bacteria, such as those of the genus Listeia or Shigella are simply able to escape the phagolysosome and go to the cellular cytoplasm where they are replicated.1

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